Process for preparing 4-substituted imidazo[1,2-a]quinoxalines

ABSTRACT

Preparation of 4-substituted imidazo[1,2-a]quinoxalines by cyclizing a compound of the formula: ##STR1## with phosphorous oxychloride wherein X 2  is a group --R 5  or --NHR 2  where R 5  and R 2  are hydrogen or various organo groups.

RELATED CASES

This is a continuation-in-part of application Ser. No. 757,640 filed Jan. 7, 1977, now abandoned.

This invention relates to certain 4-substituted imidazo[1,2-a]quinoxalines and to processes for preparing the same. It also concerns certain 1-(2-acylaminophenyl)imidazoles which among other things are useful as intermediates in the preparation of 4-substituted imidazo[1,2-a]quinoxalines. The aforesaid compounds are useful for a variety of purposes which will be described in more detail below. Some of these are useful as immunosuppressants; whereas, others are useful as anti-inflammatory agents or display antifungal activity. Moreover, some exhibit two or all three of these activities.

The 4-substituted imidazo[1,2-a]quinoxalines encompassed in the present invention may be described by the formula: ##STR2## and pharmaceutically acceptable salts thereof wherein X is --R¹ and --NHR² wherein:

(1) R¹ is bonded to a ring carbon by a carbon-to-carbon linkage and is an aliphatic, cycloaliphatic, substituted phenyl, fused bicyclic aryl; or monocyclic aryl-substituted aliphatic; and

(2) R² is a radical bonded to a nitrogen by a carbon to nitrogen linkage; said radical being selected from the group consisting of aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl or a monocyclic aryl-substituted aliphatic group.

When R¹ is an aliphatic group, it may be a straight chain or branched chain hydrocarbon group which is saturated, monounsaturated or polyunsaturated. It may also comprise a straight chain or branched chain group containing other than carbon-to-carbon bondings e.g. ether linkages, carbon to halogen linkages, etc. Ordinarily, it will contain from about 1 to 18 carbon atoms, the most typical radicals of this group being the alkyl radicals having from 1 to 18 carbon atoms.

By way of illustrating the aliphatic groups that may be represented by R¹, the following are given: CH₃ --; CH₃ CH₂ --; CH₃ CH₂ --CH₂ --; CH₃ (CH₂)_(n) -- in which n is 3, 4, 5, 6, 7, 8, 14 and 16 respectively; (CH₃)₂ CH--CH₂ --; CH₃ (CH₂)₃ (CH₃ CH₂)CH--, CH₂ ═CH--(CH₂)₈ --, alkoxyalkyl in which the alkyl moieties have from 1 to 4 carbon atoms e.g. methoxymethyl; halogenoalkyl (i.e. CH₂ Cl--; CH₃ CHCl--; CHCl₂ --; CCl₃ --; CH₂ Br--; CF₃).

When R¹ is a cycloaliphatic radical it will most often be a cycloalkyl radical containing 3 to 8 carbon atoms or a cycloalkenyl radical containing 5 to 6 carbon atoms. By way of illustrating the cycloaliphatic radicals that may correspond to R¹ in formula I mention may be made of the ##STR3##

When R¹ is a substituted phenyl radical in formula I above, the phenyl group may have from 1 to 5 substituents but will usually be mono, di or trisubstituted. Typical among the groups that may be contained in the phenyl group are (a) alkyl groups which are branched or straight chain containing 1 to 6 carbon atoms e.g. methyl, ethyl, tertiary butyl; (b) alkoxyl groups containing 1 to 6 carbon atoms e.g. methoxy, ethoxy; (c) hydroxy; (d) acyloxy containing 1 to 18 carbon atoms; (e) halogen e.g. 1 or 2 Cl, F, Br, I preferably in the meta and/or para position; (f) nitro; (g) amino; (h) acylamino in which the acylamino moiety is derived from an alkanoic acid containing 1 to 18 carbon atoms and benzamides in which the benzene ring is unsubstituted or monosubstituted, disubstituted or trisubstituted with alkyl groups containing 1 to 5 carbon atoms or halogen atoms; (i) polyhydroxyalkylamino groups containing 4 to 8 carbon atoms; (j) cyano; (k) trifluoromethyl; (l) mercapto; (m) alkylthio; (n) acylthio containing 1 to 18 carbon atoms; (o) carboxyl; (p) carboalkoxyl containing 1 to 8 aliphatic carbon atoms; (q) phenyl; (r) phenoxy, and combinations thereof.

When R¹ is a fused bicyclic aryl radical, it may be a substituted or unsubstituted radical. These are exemplified by such fused bicyclic hydrocarbon radicals as 1-napthyl, 2-napthyl, etc.

When R¹ is a monocyclic aryl substituted aliphatic radical, the monocyclic aryl moiety may be either of the substituted or unsubstituted variety. The aliphatic moiety of this group may be either of the saturated or unsaturated straight chain or branched chain hydrocarbon variety or it may contain other than carbon-to-carbon bonding. This may be illustrated by such groups as phenoxymethyl; benzyl, styryl, ##STR4##

The group R² in the radical --NHR² of formula I above is exemplified by the same radicals given above in illustrating the radical --R¹. In addition, R² may also be phenyl as in the case of the group ##STR5##

In general, the compounds included in formula I above as well as the cases in formula I in which X is hydrogen or phenyl may be prepared by heating the corresponding 1-(2-acylaminophenyl)imidazole at reflux in the presence of cyclizing quantities of a cyclizing agent e.g. polyphosphoric acid or phosphorous oxychloride, etc. for sufficient time to cause significant cyclization of this reactant. More particularly, the 1-(2-acylaminophenyl)imidazole reactants that can be employed in this process may be described by the general formula: ##STR6## in which X² is R⁵ or --NMR² wherein:

R⁵ is hydrogen or an aliphatic, cycloaliphatic, phenyl or substituted phenyl, fused bicyclic aryl or monocyclic aryl substituted aliphatic radical and R² has the same values assigned to it in connection with formula I above.

The group R⁵ in formula II is illustrated by the same groups that illustrate R¹ in formula I. However, in addition, R⁵ may also be illustrated by the phenyl radical.

The reaction can be depicted by the following equation: ##STR7##

The process of equation III is preferably carried out in the presence of an excess of an organic amine solvent. A variety of solvents may be used for this purpose among which mention may be made of the following: pyridine, 2,6-dimethylpyridine, N,N-dimethylaniline, trimethylamine, and N-methylmorpholine, etc. However, the preferred organic solvent is pyridine.

The quantity of phosphorous oxychloride that is employed in the reaction can vary somewhat. Generally, however, the phosphorous oxychloride will be employed in the range of from about one-half mole to about 6 moles and preferably one-half mole to two moles per mole of compound II.

The desired product IV may be recovered from the reaction mixture using any of the ordinary techniques well known to those skilled in this art. The time of reaction will vary depending upon, among other things, the particular reactants or molar quantities of reactants employed. In general, the reaction time will be from about 30 to 120 minutes.

The temperature employed in carrying out the reaction will also vary depending upon the particular reactants selected, the solvent and other factors. Ordinarily, the temperature employed will be the reflux temperature of the reaction mixture. This generally will be in the range of from about 95° C. to 195° C.

The method of preparing the 1-(2-acylaminophenyl)imidazoles (compound II) will vary depending on the particular type that is being made. Thus, for example, in preparing compound of the general type: ##STR8## where R⁵ is hydrogen, aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl or monocyclic aryl substituted aliphatic group, the 1-(2-acylaminophenyl)imidazole is reacted with the appropriate acid halide e.g. the acid chloride. This can be expressed by the following equation: ##STR9## in which R⁵ has the value ascribed to it above.

The reaction will usually be carried out employing equimolar amounts of the appropriate acid chloride and in the presence of excess solvent (e.g. pyridine) at reflux.

When the compounds in question are of the phenylureylene type e.g. ##STR10## wherein R² is hydrogen, aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl or monocyclic aryl substituted aliphatic group, these are prepared by reacting the aminophenylimidazole with the appropriate isocyanate. This can be expressed by the following equation: ##STR11## in which R² has the value ascribed to it above. This reaction is preferably carried out in the presence of a solvent and at steam bath temperatures. A typical solvent that can be employed is toluene and the reactants are usually used in about equimolar quantities. The products obtained from reactions VI and VIII may be recovered using standard techniques well known to those skilled in this art.

PRIOR ART

U.S. Pat. No. 3,887,566 discloses imidazo[1,2-a]quinoxaline and 4-phenylimidazo[1,2-a]quinoxaline. However, this reference does not disclose the 4-substituted imidazo[1,2-a]quinoxalines of the present invention nor the process for making these compounds. The activity disclosed in this reference for these compounds is as cardiovascular drugs. There is no disclosure of the fact that these compounds may have immunosuppressant activity, antifungal activity or non-steroidal anti-inflammatory action. It is in fact interesting to note that the unsubstituted imidazo[1,2-a]quinoxaline lacks immunosuppressant activity while the 4-phenylimidazo[1,2-a]quinoxaline has only minor activity which is greatly increased by substitution on the para- and meta- positions on the benzene ring.

Uryukina et al, Khim. Geterotsikl. Soedin., 1972, 1558-60 (See C.A. 78, 58345^(t) (1973) discloses the unsubstituted and the 7-methyl, methoxy, and bromo substituted imidazo[1,2-a]quinoxalines. No 4-substituted products are disclosed nor is any utility disclosed for these compounds.

Kovalev et al, Farmakol, Toksikol (Moscow), 36 (2), 232-238, 1973 (See C.A. 78 154693^(a)) also discloses the 7-methoxyimidazo[1,2-a]quinoxaline and suggests the use of this material as an hypotensive agent. This reference likewise does not disclose the 4-substituted imidazo[1,2-a]quinoxalines of the present invention or their utility.

Japanese Pat. Nos. 10677/74 and 10678/74 disclose certain 4-substituted 1,2-dihydroimidazo[1,2-a]quinoxalines and the fact that these materials are useful as anti-inflammatory agents. These references do not show the unhydrogenated compounds of this invention. Moreover, no immunosuppressant activity or antifungal activity is disclosed.

Siminov et al, Khim. Geterotsikl, Soedin, 7, 570 (1971) (See C.A. 76, 25242^(n) 1972) discloses a process for synthesizing imidazo[1,2-a]quinoxaline involving the reduction of 1-(o-nitrophenyl)-2-formylimidazole. This is obviously not related to the process of the present invention.

The following Examples are given to further illustrate the present invention. It is to be understood, however, that they are not limitative of this invention.

The compounds described in the Tables below were prepared as described. Melting points were obtained by the capillary tube method using a Mel-Temp melting point apparatus and are uncorrected. Ultraviolet spectra were obtained in ethanol solution using a Beckman U.V. Acta III or a Beckman DBG. 1-(2-aminophenyl)imidazole was prepared as reported by A. F. Pozharskii, A. M. Siminov and L. M. Sitkina, Khim. Geterotskl. Soedin. 5, 1916 (1969) [chem. Abstr., 72 11427^(a) (1970)].

Table I below further illustrates the preparation of the aliphatic, cycloaliphatic and monocyclic aryl substituted aliphatic- amidophenylimidazoles of the present invention. Table II further exemplifies the preparation of the aryl (including the fused ring aryl) amidophenylimidazoles of this invention.

Except as noted in Tables I and II, the amides were prepared by reacting equimolar amounts of the appropriate acid chloride with 1-(2-aminophenyl)imidazole in the presence of excess pyridine on a steam bath for 45 minutes. The reaction mixture was then stirred into ice water and the crude product isolated according to one of the following methods.

Method A

If a solid was obtained, it was directly crystallized from the solvent indicated in Table I.

Method B

If an oil was obtained, it was dissolved in a minimum amount of chloroform and passed through an alumina column with the amount of alumina being approximately twenty times the weight of the crude solid; elution was with chloroform. The chloroform was evaporated from the crude product which was crystallized as indicated in Table I.

Method C

If a solution was obtained in the ice water mixture, the pyridine/water azeotrope was removed until the crude product separated. It was then treated as in Method B above.

                                      TABLE I                                      __________________________________________________________________________      ##STR12##                                                                     1-(2-alkanamidophenyl)imidazoles                                                                     Isolation                                                                           %   Crystallization                                                                               Analysis                         No.                                                                               R                  Method                                                                              Yield                                                                              Solvent  m.p., °C.                                                                     Calc'd                                                                              Found                       __________________________________________________________________________     1  H.sup.a            C    63.3                                                                               Water    200-204                                                                              C,64.16                                                                             64.26                                                                     H, 4.85                                                                              4.71                                                                     N,22.45                                                                             22.30                       2  CH.sub.3           A    56.2                                                                               Ethanol  163-166                                                                              C,65.66                                                                             65.69                                                                     H, 5.51                                                                              5.52                                                                     N,20.88                                                                             20.84                       3  CH.sub.3 CH.sub.2.sup.b                                                                           C    73.9                                                                               Water    144-146                                                                              C,66.96                                                                             67.26                                                                     H, 6.09                                                                              6.15                                                                     N,19.52                                                                             19.40                       4  CH.sub.3 (CH.sub.2).sub.2                                                                         B    31.1                                                                               Toluene  108-110                                                                              C,68.10                                                                             67.95                                                                     H, 6.59                                                                              6.52                                                                     N,18.33                                                                             18.25                       5  CH.sub.3 (CH.sub.2).sub.3                                                                         B    49.6                                                                               Toluene- 123-125                                                                              C,69.11                                                                             69.14                                                      hexane         H, 7.04                                                                              7.00                                                                     N,17.27                                                                             17.17                       6  CH.sub.3 (CH.sub.2).sub.4                                                                         B    49.4                                                                               isopropyl ether-                                                                        103-105                                                                              C,70.01                                                                             70.31                                                      trichloroethylene                                                                             H, 7.44                                                                              7.45                                                                     N,16.33                                                                             16.26                       7  CH.sub.3 (CH.sub.2).sub.5                                                                         A    55.3                                                                               isopropyl ether                                                                          96-98                                                                               C,70.82                                                                             70.79                                                                     H, 7.80                                                                              7.74                                                                     N,15.48                                                                             15.23                       8  CH.sub.3 (CH.sub.2).sub.6                                                                         A    55.1                                                                               isopropyl ether                                                                         101-102                                                                              C,71.55                                                                             71.67                                                                     H, 8.12                                                                              8.05                                                                     N,14.72                                                                             14.65                       9  CH.sub.3 (CH.sub.2).sub.7                                                                         A    45.6                                                                               isopropyl ether                                                                          93-95                                                                               C,72.21                                                                             72.24                                                                     H, 8.42                                                                              8.41                                                                     N,14.03                                                                             13.92                       10 CH.sub.3 (CH.sub.2).sub.8                                                                         A    60.6                                                                               isopropyl                                                                                79-81                                                                               C,72.81                                                                             73.38                                                      ether-hexane   H, 8.68                                                                              8.85                                                                     N,13.41                                                                             13.02                       11 CH.sub.3 (CH.sub.2).sub.14                                                                        B    58.1                                                                               isopropyl ether                                                                          94-96                                                                               C,75.52                                                                             75.12                                                                     H, 9.89                                                                              9.76                                                                     N,10.57                                                                             10.38                       12 CH.sub.3 (CH.sub.2).sub.16                                                                        B    80.6                                                                               isopropyl ether                                                                          98-100                                                                              C,76.19                                                                             76.57                                                                     H,10.18                                                                             10.28                                                                     N, 9.87                                                                              9.79                       13 (CH.sub.3).sub.3 C.sup.b                                                                          C    48.8                                                                               benzene  102-104                                                                              C,69.11                                                                             69.15                                                                     H, 7.04                                                                              7.26                                                                     N,17.27                                                                             17.19                       14 (CH.sub.3).sub.2 CHCH.sub.2                                                                       C    25.4                                                                               benzene  128-130                                                                              C,69.40                                                                             69.60                                                                     H, 6.66                                                                              7.00                                                                     N,17.34                                                                             17.40                       15 CH.sub.3 (CH.sub.2).sub.3 (CH.sub.3 CH.sub.2)CH                                                   B    32.8                                                                               benzene  125-127                                                                              C,71.55                                                                             71.86                                                                     H, 8.12                                                                              7.84                                                                     N,14.72                                                                             14.95                       16 CH.sub.2CH(CH.sub.2).sub.8                                                                        A    76.8                                                                               isopropyl                                                                                92-94                                                                               C,73.81                                                                             74.26                                                      ether-hexane   H, 8.36                                                                              8.50                                                                     N,12.91                                                                             12.30                       17 CH.sub.3 (CH.sub.2).sub.3 (CH.sub.2CHCH).sub.2 (CH.sub.2).sub.7                                   C     3.6                                                                               C.        73.76                                                                               C,76.92                                                                             76.73                                                                     H, 9.32                                                                              9.36                                                                     N, 9.97                                                                              9.78                       18                                                                                 ##STR13##         C    41.9                                                                               ethanol  145.147                                                                              C,73.63 H, 5.45 N,15.15                                                             73.81  5.57 15.41           19                                                                                 ##STR14##         C     7.7                                                                               diethyl ether                                                                           205-207                                                                              C,74.73 H, 6.27 N,13.76                                                             74.83  6.32 13.59           20                                                                                 ##STR15##         A    43.0                                                                               ethanol  161-164                                                                              C,74.72 H, 5.23 N,14.52                                                             74.94  5.47 14.55           21 CH.sub.3 OCH.sub.2 A    49.8                                                                               Toluene  146-147                                                                              C,62.33                                                                             61.99                                                                     H, 5.66                                                                              5.74                                                                     N,18.17                                                                             18.48                       22                                                                                 ##STR16##         A    77.7                                                                               Toluene  136.5- 138.5                                                                         C,69.61 H, 5.15 N,14.33                                                             69.82  5.37 14.04           23                                                                                 ##STR17##         A    10.1                                                                               isopropanol                                                                             207-209                                                                              C,68.71 H, 5.76 N,18.49                                                             68.67  5.85 18.67           24                                                                                 ##STR18##         A    55.6                                                                               Toluene  151-153                                                                              C,69.69 H, 6.27 N,17.41                                                             69.44  6.21 17.55           25                                                                                 ##STR19##         A    67.3                                                                               Toluene  142.5- 145                                                                           C,71.35 H, 7.11 N,15.60                                                             70.88  6.92 15.59           26                                                                                 ##STR20##         A    21.6                                                                               ethanol  196-198.5                                                                            C,72.16 H, 6.06 N,15.78                                                             71.87  6.33 15.40           27 CH.sub.2 Cl        B    11.9                                                                               water    255(dec.)                                                                            C,56.06                                                                             55.92                                                                     H, 4.28                                                                              4.26                                                                     N,17.83                                                                             17.72                       28 CH.sub.3 CHCl      A    27.9                                                                               Toluene  143.5-                                                                               C,57.72                                                                             57.54                                                               145.5°                                                                        H, 4.85                                                                              4.92                                                                     N,16.83                                                                             17.16                       29 CHCl.sub.2.sup.b   A    33.2                                                                               benzene  162-165                                                                              C,48.91                                                                             48.94                                                                     H, 3.36                                                                              3.24                                                                     N,15.56                                                                             15.42                                                                     Cl,26.25                                                                            26.17                       30 CF.sub.3           A    22.0                                                                               ethanol  165-167                                                                              C,51.77                                                                             51.58                                                                     H, 3.16                                                                              3.20                                                                     N,16.47                                                                             16.53                       32                                                                                 ##STR21##         C    14.1                                                                               trichloro- ethylene                                                                     128-130                                                                              C,60.23 H, 5.05 N,16.21                                                             60.21  5.10 16.16           __________________________________________________________________________      Notes:                                                                         .sup.a Prepared from aceticformic anhydride according to R. J. Jones, J.       Am. Chem. Soc., 71,644(1949). After removal by distillation of excess          solvent, residue dissolved in water and neutralized with NaOH to provide       crude product.                                                                 .sup.b Prepared via the anhydride.                                             .sup.c Could not be crystallized; purified by chromatography on alumina        with ethyl acetate as elutant.                                           

                                      TABLE II                                     __________________________________________________________________________      ##STR22##                                                                     1-(2-Arylamidophenyl)imidazoles                                                                  Isolation                                                                           %   Crystallization           Analysis                  No. Ar            Method                                                                              Yield                                                                              Solvent     m.p., °C.                                                                      λmax.                                                                          Calc'd                                                                              Found                __________________________________________________________________________     34                                                                                  ##STR23##    A    44.9                                                                               dimethoxyethane                                                                            148-150                                                                               225(21,720)                                                                           C,72.99 H, 4.98                                                                N,15.96                                                                             73.30  5.08                                                                    16.04                35                                                                                  ##STR24##    A    58.7                                                                               ethanol     190-192.5                                                                             262(21,400)                                                                           C,73.63 H, 5.45                                                                N,15.15                                                                             73.10  5.32                                                                    15.46                36                                                                                  ##STR25##    B    58.3                                                                               benzene     147-148.5                                                                             231,sh(18,200)                                                                        C,73.63  H, 5.45                                                               N,15.15                                                                             73.63  5.24                                                                    15.36                37                                                                                  ##STR26##    B    57.4                                                                               benzene     143-146.5                                                                             236(23,400)                                                                           C,73.63 H, 5.45                                                                N,15.15                                                                             73.28  5.29                                                                    15.27                38                                                                                  ##STR27##    A    53.0                                                                               benzene     151-153                                                                               .sup.c C,61.63 H, 3.65                                                                N,12.68                                                                             60.97  3.62                                                                    12.34                39                                                                                  ##STR28##    B    79.3                                                                               ethyl acetate                                                                              136-138                                                                               239(20,400)                                                                           C,75.21 H, 6.63                                                                N,13.27                                                                             75.06  6.45                                                                    13.31                40                                                                                  ##STR29##    A    45.5                                                                               isopropanol 198-200                                                                               276(28,100)                                                                           C,77.86 H, 5.05                                                                N,12.38                                                                             77.46  4.76                                                                    12.09                41                                                                                  ##STR30##    A    73.5                                                                               dimethylfoemamide, ethanol                                                                 194-196                                                                               260(17,810)                                                                           C,62.33 H, 3.92                                                                N,18.17                                                                             62.26 3.69                                                                     18.10                42                                                                                  ##STR31##    A    74.4                                                                               dimethylformamide, water                                                                   198-202.5                                                                             250(16,500)                                                                           C,62.33 H, 3.92                                                                N,18.17                                                                             62.27  4.00                                                                    18.37                43                                                                                  ##STR32##    A    87.41                                                                              dimethylformamide, water                                                                   254-256                                                                               .sup.c C,54.40 H, 3.14                                                                N,19.82                                                                             54.35  3.31                                                                    19.82                44                                                                                  ##STR33##    A    60.87                                                                              dimethylformamide, water                                                                   219-220.5                                                                             234(1,500)                                                                            C,70.82 H, 4.20                                                                N,19.49                                                                             70.14  4.45                                                                    19.15                45                                                                                  ##STR34##    B    56.8                                                                               benzene     205-208                                                                               229(18,500)                                                                           C,68.32 H, 4.30                                                                N,14.94                                                                             67.86  4.02                                                                    15.17                46                                                                                  ##STR35##    A    .sup. 53.2.sup.a                                                                   dimethylformamide, water                                                                    93-96 260(10,100)                                                                           C,66.20 H, 4.51                                                                N,14.47                                                                             65.96  4.37                                                                    14.40                47                                                                                  ##STR36##    A    .sup.b                                                                             dimethylformamide                                                                          189-190.5                                                                             240(22,100)                                                                           C,56.16 H, 3.53                                                                N,12.28                                                                             56.03  3.58                                                                    12.51                48                                                                                  ##STR37##    A    40.1                                                                               dimethylformamide, water                                                                   199-201.5                                                                             258(20,100)                                                                           C,56.16 H, 3.54                                                                N,12.28                                                                             55.84  3.58                                                                    12.48                                                                           A#38.78dimethyl                                                               formamide,                                                                     ethanol 210-203                                                                (261(16,700) C,6                                                               4.54 H, 4.06                                                                   N,14.11 64.70                                                                  4.05 13.95           50                                                                                  ##STR39##    B    68.5                                                                               ethanol     144-146                                                                               .sup.c C,64.54 H, 4.06                                                                N,14.11                                                                             64.82  3.92                                                                    14.59                51                                                                                  ##STR40##    A    59.7                                                                               ethanol     167-170                                                                               240(26,410)                                                                           C,64.54 H, 4.06                                                                N,14.11                                                                             64.41  3.94                                                                    13.92                52                                                                                  ##STR41##    A    26.6                                                                               dimethylformamide, water                                                                   210-212                                                                               265(21,000)                                                                           C,57.85 H, 3.34                                                                N,12.65                                                                             58.05  3.46                                                                    13.08                53                                                                                  ##STR42##    A    61.2                                                                               dimethylformamide, water                                                                   180.5-183                                                                             235(22,100)                                                                           C,57.85 H, 3.34                                                                N,12.65                                                                             57.65  3.51                                                                    12.93                54                                                                                  ##STR43##    A    42.9                                                                               ethanol     186.5-189                                                                             255(28,480)                                                                           C,49.38  H, 3.11                                                               N,10.80 I,                                                                          49.22  3.15                                                                    10.85 32.89          55                                                                                  ##STR44##    B    58.6                                                                               isopropanol 146-151                                                                               263(20,400)                                                                           C,69.61 H, 5.15                                                                N,14.33                                                                             69.01  5.14                                                                    14.36                56                                                                                  ##STR45##    B    83.2                                                                               dimethylformamide, water                                                                   171-173                                                                               281(5,100)                                                                            C,69.61 H, 5.15                                                                N,14.33                                                                             69.27  5.02                                                                    14.28                57                                                                                  ##STR46##    B    61.2                                                                               benzene     130-132.5                                                                             244,sh(12,300)                                                                        C,66.86 H, 5.30                                                                N,13.00                                                                             66.97  5.08                                                                    13.54                58                                                                                  ##STR47##    C    29.79                                                                              dimethylformamide, water                                                                   133.5-136.5                                                                           281(15,410)                                                                           C,69.61 H, 5.15                                                                N,14.33                                                                             69.10  5.08                                                                    14.18                59                                                                                  ##STR48##    B    18.26                                                                              dimethylformamide, water                                                                   164.5-166.5                                                                           .sup.c C,56.16 H, 3.54                                                                N,12.28                                                                             55.65  3.51                                                                    12.37                60                                                                                  ##STR49##    A    51.07                                                                              isopropanol 142.5-145.5                                                                           223(14,420)                                                                           C,68.32 H, 4.30                                                                N,14.94                                                                             67.79  4.36                                                                    14.58                61                                                                                  ##STR50##    B    15.68                                                                              isopropanol- ethanol                                                                       203.5-205                                                                             258(18,840)                                                                           C,54.40 H, 2.28                                                                N,11.90                                                                             53.78  2.30                                                                    12.16                62                                                                                  ##STR51##    A    46.9                                                                               isopropanol 165.5-167.5                                                                           237(53,900)                                                                           C,76.66 H, 4.83                                                                N,13.41                                                                             76.29  4.84                                                                    13.27                63                                                                                  ##STR52##    A    36.78                                                                              isopropanol- dimethylformamide                                                             175-177                                                                               289(6,940)                                                                            C,76.66 H, 4.82                                                                N,13.41                                                                             76.68  4.75                                                                    12.01                190                                                                                 ##STR53##    B    38.80                                                                              benzene     156-157.5                                                                             268(13,800)                                                                           C,64.58 H, 5.42                                                                N,11.89                                                                             64.58  5.39                                                                    12.02                217                                                                                 ##STR54##    A    45.8                                                                               ethanol     134-136.5                                                                             273(14,900)                                                                           C,66.86  H, 5.30                                                               N,13.00                                                                             66.88  5.37                                                                    12.68                __________________________________________________________________________      Notes:                                                                         .sup.a isolated as hemihydrate.                                                .sup.b partial loss prevented yield determination.                             .sup.c Compound absorbed too low for significant U.V.                    

Alkyl-2-(1-imidazolyl)phenylureylenes (Table III) were prepared by the reaction of equimolar amounts of the aminophenylimidazole and the appropriate isocyanate in toluene solution at steam bath temperatures during two or three hours. Upon cooling, the crude product was collected by filtration and treated by one of the following methods: (A) direct crystallization from the appropriate solvent or (B) dissolved in hot dimethylformamide and precipitated with water followed by crystallization.

                                      TABLE III                                    __________________________________________________________________________      ##STR55##                                                                     Alkyl-2-(1-imidazolyl)phenylureylenes                                                       Isolation                                                                           %   Crystallization       Analysis                           No.                                                                               R         Method                                                                              Yield                                                                              Solvent   m.p., °C.                                                                    λmax. (Am)                                                                     Calc'd                                                                             Found                          __________________________________________________________________________     64 CH.sub.3  A    41.6                                                                               ethanol   194-196                                                                             240(15,500)                                                                           C,61.60                                                                            61.22                                                                      H, 5.59                                                                             5.48                                                                      N,25.91                                                                            26.11                          65 CH.sub.3 CH                                                                              B    27.3                                                                               trichloroethylene                                                                        173-175                                                                             278(1,200)                                                                            C,62.59                                                                            62.21                                                               242(12,700)                                                                           H, 6.13                                                                             6.04                                                                      N,24.33                                                                            24.32                          66 CH.sub.3 CH.sub.2 CH.sub.2                                                               B    49.3                                                                               trichloroethylene                                                                        139-141                                                                             279(1,200)                                                                            C,63.92                                                                            63.75                                                               240(12,800)                                                                           H, 6.60                                                                             6.56                                                                      N,22.93                                                                            23.00                          67 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                      B    35.6                                                                               isopropanol                                                                              115-116.5                                                                           278(1,400)                                                                            C,65.09                                                                            64.84                                                               241(15,000)                                                                           H, 7.02                                                                             7.00                                                                      N,21.69                                                                            21.78                          68                                                                                 ##STR56##                                                                               A    50.64                                                                              dimethylformamide, water                                                                 164-166                                                                             241(12,200)                                                                           C,67.58 H, 7.09 N,19.70                                                            67.60  7.08 19.44              __________________________________________________________________________

Aryl-2-(1-imidazolyl)phenylureylenes (Table IV) were prepared by reacting equimolar amounts of the aminophenylimidazole and the appropriate arylisocyanate in dry toluene during three hours at steam bath temperatures. The reaction mixture was cooled and the crude product was separated by filtration, and washed with ether and crystallized from the indicated solvent.

                                      TABLE IV                                     __________________________________________________________________________      ##STR57##                                                                     Aryl-2-(1-imidazolyl) phenylureylenes                                                                      Recrystallization         Analysis                 No. Ar                % Yield                                                                              Solvent     m.p. °C.                                                                       λmax.                                                                          Calc'd                                                                              Found               __________________________________________________________________________     69                                                                                  ##STR58##        64.6  ethanol     201-203                                                                               256(27,640)                                                                           C,69.05 H, 5.07                                                                N,20.13                                                                             69.13  5.15                                                                    20.16               70                                                                                  ##STR59##        76.9  dimethylformamide- water                                                                   203.5-207.5                                                                           258(23,400)                                                                           C,69.84 H, 5.52                                                                N,19.17                                                                             69.85  5.47                                                                    19.28               71                                                                                  ##STR60##        76.9  ethanol     182-183.5                                                                             256(25,800)                                                                           C,69.84 H, 5.52                                                                N,19.17                                                                             69.97  5.35                                                                    19.12               72                                                                                  ##STR61##        78.8  dimethylformamide- water                                                                   202.5-203.5                                                                           251(25,500)                                                                           C,64.86 H, 4.42                                                                N,18.91                                                                             64.77  4.47                                                                    19.16               73                                                                                  ##STR62##        61.9  dimethylformamide- water                                                                   201-202                                                                               253(26,000)                                                                           C,64.86 H, 4.42                                                                N,18.97                                                                             64.47  4.40                                                                    19.24               74                                                                                  ##STR63##        65.8  dimethylformamide- water                                                                   220-222                                                                               251(23,100)                                                                           C,64.86 H, 4.42                                                                N,18.97                                                                             64.56  4.41                                                                    19.14               75                                                                                  ##STR64##        76.7  dimethylformamide- water                                                                   204-206                                                                               258(30,900)                                                                           C,61.45 H, 4.19                                                                N,17.91                                                                             61.57  4.12                                                                    18.26               76                                                                                  ##STR65##        58.1  dimethylformamide- water                                                                   244-245.5                                                                             260(32,900)                                                                           C,55.35 H, 3.48                                                                N,16.14                                                                             54.93  3.47                                                                    16.25               77                                                                                  ##STR66##        70.0  dimethylformamide- water                                                                   180.5-182.5                                                                           252(23,000)                                                                           C,53.80 H, 3.76                                                                N,15.68                                                                             53.88  3.78                                                                    15.66               78                                                                                  ##STR67##        75.2  dimethylformamide- water                                                                   218-219.5                                                                             258(28,600)                                                                           C,53.80 H, 3.67                                                                N,15.68                                                                             53.71  3.66                                                                    15.35               79                                                                                  ##STR68##        53.1  methanol    227-230.5                                                                             260(27,700)                                                                           C,53.80 H, 3.67                                                                N,15.68                                                                             52.08  3.56                                                                    15.12               80                                                                                  ##STR69##        83.2  dimethylformamide- water                                                                   201-202                                                                               253(26,000)                                                                           C,64.86 H, 4.42                                                                N,18.97                                                                             64.47  4.40                                                                    19.24               81                                                                                  ##STR70##        57.79 dimethylformamide- water                                                                   167-170                                                                               250(20,710)                                                                           C,69.84 H, 5.52                                                                N,19.17                                                                             70.10  5.57                                                                    18.60               82                                                                                  ##STR71##        77.4  dimethylformamide- water                                                                   216.5-218.5                                                                           256(31,010)                                                                           C,58.96 H, 3.78                                                                N,16.18                                                                             58.86  3.81                                                                    15.79               83                                                                                  ##STR72##        78.9  dimethylformamide- water                                                                   212-215                                                                               260(27,580)                                                                           C,70.57 H, 5.92                                                                N,18.29                                                                             70.30  5.83                                                                    18.00               84                                                                                  ##STR73##        76.6  dimethylformamide- water                                                                   185-188                                                                               258(29,590)                                                                           C,70.57 H, 5.92                                                                N,18.29                                                                             70.30  5.96                                                                    18.00               85                                                                                  ##STR74##        76.2  dimethylformamide- water                                                                   163.5-166                                                                             258(28,770)                                                                           C,70.57 H, 5.92                                                                N,18.29                                                                             70.52  5.81                                                                    17.94               86                                                                                  ##STR75##        67.8  dimethylformamide- water                                                                   169-172                                                                               257(29,920)                                                                           C,71.83 H, 6.63                                                                N,16.75                                                                             71.61  6.56                                                                    16.24               87                                                                                  ##STR76##        80.6  dimethylformamide- water                                                                   206-209                                                                               282(27,620)                                                                           C,71.23 H, 6.29                                                                N,17.49                                                                             71.12  6.12                                                                    17.24               88                                                                                  ##STR77##        69.0  dimethylformamide- water                                                                   204.5-206                                                                             285(10,630)                                                                           C,66.22 H, 5.23                                                                N,18.17                                                                             65.96  5.15                                                                    18.15               89                                                                                  ##STR78##        84.0  dimethylformamide- water                                                                   188    252(25,510)                                                                           C,66.22 H, 5.23                                                                N,18.17                                                                             65.83  5.13                                                                    18.02               90                                                                                  ##STR79##        81.9  dimethylformamide- water                                                                   200-202                                                                               260(24,560)                                                                           C,66.22 H, 5.23                                                                N,18.17                                                                             65.61  5.14                                                                    17.98               91                                                                                  ##STR80##        80.9  dimethylformamide- water                                                                   190.5-193                                                                             259(27,180)                                                                           C,67.07 H, 5.63                                                                N,17.38                                                                             66.80  5.62                                                                    17.16               92                                                                                  ##STR81##        79.5  dimethylformamide- water                                                                   178-179.5                                                                             258(26,490)                                                                           C,68.55 H, 6.33                                                                N,15.99                                                                             68.68  6.34                                                                    15.62               93                                                                                  ##STR82##        64.1  dimethylformamide- water                                                                   202.5-205                                                                             259(35,850)                                                                           C,71.34 H, 4.90                                                                N,15.13                                                                             71.14  4.93                                                                    14.78               94                                                                                  ##STR83##        75.1  dimethylformamide- water                                                                   189-191                                                                               278(32,130)                                                                           C,62.94 H, 4.97                                                                N,17.27                                                                             62.84  4.86                                                                    17.22               95                                                                                  ##STR84##        62.3  dimethylformamide- water                                                                   211.5-214.5                                                                           259(30,210)                                                                           C,61.45 H, 4.19                                                                N,17.91                                                                             60.94  4.02                                                                    17.79               96                                                                                  ##STR85##        75.9  dimethylformamide- water                                                                   198-210                                                                               252(25,230)                                                                           C,61.44 H, 3.85                                                                N,17.83                                                                             61.33  3.92                                                                    17.98               97                                                                                  ##STR86##        64.8  dimethylformamide- water                                                                   232.5-234                                                                             258(32,380)                                                                           C,55.35 H, 3.48                                                                N,16.14                                                                             55.60  3.50                                                                    16.00               98                                                                                  ##STR87##        70.7  dimethylformamide- water                                                                   237.5-239                                                                             258(31,300)                                                                           C,62.48 H, 4.63                                                                N,17.15                                                                             62.79  4.70                                                                    17.30               99                                                                                  ##STR88##        70.0  dimethylformamide- water                                                                   229-232                                                                               256(25,630)                                                                           C,58.10 H, 3.66                                                                N,16.94                                                                             57.84  3.56                                                                    16.90               100                                                                                 ##STR89##        57.6  dimethylformamide- water                                                                   239.5-242.2                                                                           261(37,430)                                                                           C,53.63 H, 3.18                                                                N,14.71                                                                             53.89  3.05                                                                    14.41               101                                                                                 ##STR90##        50.7  dimethylformamide- water                                                                   190-192                                                                               255(26,350)                                                                           C,53.63 H, 3.18                                                                N,14.71                                                                             53.70  2.97                                                                    14.90               102                                                                                 ##STR91##        42.7  dimethylformamide- water                                                                   202-205                                                                               375(4,200) 253(32,970)                                                                C,59.44 H, 4.05                                                                N,21.66                                                                             59.40  4.10                                                                    21.44               103                                                                                 ##STR92##        44.2  dimethylformamide- water                                                                   237.5-239-5                                                                           342(1,800) 264(46,530)                                                                C,59.44 H, 4.05                                                                N,21.66                                                                             59.16  4.10                                                                    21.31               104                                                                                 ##STR93##        52.3  dimethylformamide- water                                                                   >257(Dec.)                                                                            330(20,010)                                                                           C,59.44 H, 4.05                                                                N,21.66                                                                             59.01  3.97                                                                    21.07               105                                                                                 ##STR94##        35.4  dimethylformamide- water                                                                   256.5-258                                                                             257(33,080)                                                                           C,53.72 H, 3.38                                                                N,19.57                                                                             53.72  3.31                                                                    19.63               106                                                                                 ##STR95##        57.1  dimethylformamide- water                                                                   254-256 (Dec.)                                                                        256(36,930)                                                                           C,60.53 H, 4.48                                                                N,20.76                                                                             60.26  4.34                                                                    20.68               107                                                                                 ##STR96##        47.3  dimethylformamide- water                                                                   244    290(57,510)                                                                           C,67.32 H, 4.32                                                                N,23.09                                                                             67.88  4.13                                                                    21.37               108                                                                                 ##STR97##        33.8  dimethylformamide- water                                                                   227.5-229.5                                                                           297(32,710)                                                                           C,67.48 H, 5.03                                                                N,17.49                                                                             67.49  5.05                                                                    17.07               191                                                                                 ##STR98##        35.2  dimethylformamide- water                                                                   233-236                                                                               284(16,710)                                                                           C,73.15 H, 4.91                                                                N,17.06                                                                             72.70  4.97                                                                    16.63               192                                                                                 ##STR99##        25.2  dimethylformamide- water                                                                   231-232                                                                               252(32,920)                                                                           C,56.31 H, 3.55                                                                N,20.52                                                                             54.13  3.50                                                                    20.21               __________________________________________________________________________

4-Alkylimidazo[1,2-a]quinoxalines (Table V) were prepared by refluxing the appropriate amide (Table I, compounds 1-33) with phosphorous oxychloride in excess pyridine during one hour. The reaction mixture was stirred into water and sufficient azeotrope removed to form a viscous residue which was dissolved in chloroform, dried over MgSO₄, and chromatographed through an alumina column. The chloroform was evaporated and the product crystallized from the indicated solvent.

                                      TABLE V                                      __________________________________________________________________________      ##STR100##                                                                    4-alkylimidazo[1,2-a] quinoxalines                                                                  Recrystallization    Analysis                             No.                                                                               R            % Yield                                                                             Solvent  m.p. °C.                                                                      λ.sub.max.(Am)                                                                Calc'd                                                                             Found                            __________________________________________________________________________     109                                                                               H a          63.3 sublimed 120   316(10,900)                                110                                                                               CH.sub.3     13.3 isopropyl ether                                                                         134-135                                                                              312(11,200)                                                                          C,72.11                                                                            72.18                                                                      H, 4.95                                                                             4.89                                                                      N,22.93                                                                            23.01                            111                                                                               CH.sub.3 CH.sub.2                                                                           37.6 hexane   114-115                                                                              311(10,500)                                                                          C,73.07                                                                            72.85                                                                      H, 5.62                                                                             5.83                                                                      N,21.30                                                                            21.29                            112                                                                               CH.sub.3 CH.sub.2 CH.sub.2                                                                  14.3 hexane   110-111                                                                              314(10,900)                                                                          C,73.91                                                                            73.99                                                                      H, 6.20                                                                             6.13                                                                      N,19.89                                                                            19.94                            113                                                                               CH.sub.3 (CH.sub.2).sub.3                                                                   17.6 hexane   92-93 324(8,000)                                                                           C,74.64                                                                            74.34                                                                      H, 6.70                                                                             6.74                                                                      N,18.65                                                                            18.48                            114                                                                               CH.sub.3 (CH.sub.2).sub.4                                                                   29.2 b.       63-65 314(11,300)                                                                          C,75.28                                                                            75.13                                                                      H, 7.16                                                                             7.39                                                                      N,17.56                                                                            17.43                            115                                                                               CH.sub.3 (CH.sub.2).sub.5                                                                   10.7 b.       43-45 313(10,800)                                                                          C,75.86                                                                            76.03                                                                      H, 7.56                                                                             7.63                                                                      N,16.59                                                                            16.40                            116                                                                               CH.sub.3 (CH.sub.2).sub.6                                                                   8.0  c.       54-57 313(9,400)                                                                           C,76.37                                                                            75.84                                                                      H, 7.92                                                                             7.77                                                                      N,15.72                                                                            16.43                            117                                                                               CH.sub.3 (CH.sub.2).sub.7                                                                   26.3 isopropyl ether                                                                         65-66 311(11,600)                                                                          C,76.83                                                                            76.97                                                                      H, 8.24                                                                             8.20                                                                      N,14.93                                                                            14.89                            118                                                                               CH.sub.3 (CH.sub.2).sub.8                                                                   9.5  ethyl ether-                                                                            55-57 307(12,500)                                                                          C,77.25                                                                            77.04                                                 hexane               H,  8.53                                                                            8.36                                                                      N,14.22                                                                            14.52                            119                                                                               CH.sub.3 (CH.sub.2).sub.14                                                                  24.3 isopropyl ether                                                                         73-75 313(11,300)                                                                          C,79.11                                                                            79.03                                                                      H, 9.82                                                                            10.02                                                                      N,11.07                                                                            10.88                            120                                                                               CH.sub.3 (CH.sub.2).sub.16                                                                  13.7 isopropyl ether                                                                         79-81 311(11,300)                                                                          C,79.11                                                                            79.54                                                                      H,10.14                                                                            10.12                                                                      N,10.31                                                                            10.34                            121                                                                               (CH.sub.3).sub.2 CHCH.sub.2                                                                 12.6 hexanes  52-55 314(11,700)                                                                          C,74.64                                                                            74.92                                                                      H, 6.71                                                                             6.81                                                                      N,18.65                                                                            18.74                            122                                                                               CF.sub.3     50.7 isopropyl ether-                                                                        184-187                                                                              328(10,800)                                                                          C,55.70                                                                            55.94                                                 chloroform           H, 2.55                                                                             2.49                                                                      N,17.72                                                                            17.64                            123                                                                               CH.sub.2CH(CH.sub.2).sub.8                                                                  9.8  hexanes  40-42 309(13,100)                                                                          C,78.14                                                                            77.92                                                                      H, 8.20                                                                             7.98                                                                      N,13.67                                                                            13.96                            124                                                                                ##STR101##  16.7 ethanol  140.5-142                                                                            312(13,100)                                                                          C,78.74 H, 5.05 N,16.20                                                            78.59  5.20 16.10                125                                                                               CH.sub.3 OCH.sub.2                                                                          3.1  toluene-hexane                                                                          96.5-97.5                                                                            312(10,600)                                                                          C,67.59                                                                            67.04                                                                      H, 5.20                                                                             5.17                                                                      N,19.71                                                                            19.93                            126                                                                                ##STR102##  14.5 ethanol  146.5-148.5                                                                          314(10,400)                                                                          C,74.17 H, 4.76 N,15.25                                                            74.28  4.61 15.00                127                                                                                ##STR103##  37.2 benzene  164-167                                                                              286(10,500)                                                                          C,79.68 H, 4.83 N,15.49                                                            80.38  4.91 15.12                128                                                                                ##STR104##  17.9 hexane   106.5-107.5                                                                          310(11,500)                                                                          C,75.31 H, 5.87 N,18.82                                                            75.32  5.84 18.75                129                                                                                ##STR105##  2.0  hexane   119-120.5                                                                            311(11,400)                                                                          C,76.46 H, 6.82 N,16.72                                                            76.65  6.76 16.58                130                                                                                ##STR106##  0.8  isopropyl ether                                                                         133-135                                                                              312(11,700)                                                                          C,77.39 H, 5.68 N,16.92                                                            77.20  6.13 16.76                __________________________________________________________________________      Notes:                                                                         a A.M.Siminov and I.G. Urykina, Khim. Geterot Soedin., 7,570(1971) report      this compound has an mp of 124° with λ.sub.max.sup.MeOH.         (Am) = 315(10,700).                                                            b. Purified by sublimation at 90°/0.15 mm Pressure.                     c. Purified by distillation at 174-184°/0.40 mm P.                

4-Arylimidazo[1,2-a]quinoxalines (Table VI) were prepared and isolated according to the general method described for the 4-alkylimidazo[1,2-a]quinoxalines, except as noted in Table VI.

                                      TABLE VI                                     __________________________________________________________________________      ##STR107##                                                                    4-Arylimidazo(1,2-a)quinoxalines                                                                           %   Crystallization          Analysis              No.                                                                               Ar                       Yield                                                                                Solvent  m.p. °C.                                                                      λmax.(Am)                                                                     Calc'd                                                                             Found               __________________________________________________________________________     131                                                                                ##STR108##              34.8                                                                               benzene    145-147                                                                              328(14,100)                                                                          C,78.35 H, 4.52                                                                N,17.13                                                                            78.70  4.38                                                                    16.90               132                                                                                ##STR109##              37.2                                                                               toluene- isopropanol                                                                      149-150.5                                                                            334(22,650)                                                                          C,78.74 H, 5.05                                                                N,16.20                                                                            78.89  5.08                                                                    16.27               133                                                                                ##STR110##              35.9                                                                               isopropanol- isopropyl ether                                                              112-114                                                                              329(15,400)                                                                          C,78.74  H, 5.05                                                               N,16.20                                                                            78.53   5.19                                                                   16.20               134                                                                                ##STR111##              47.1                                                                               isopropanol                                                                               119-120                                                                              329(18,100)                                                                          C,78.74 H, 5.05                                                                N,16.20                                                                            78.32  4.73                                                                    15.93               135                                                                                ##STR112##              37.8                                                                               isopropanol                                                                               136-137                                                                              331(27,780)                                                                          C,82.22 H, 4.70                                                                N,13.07                                                                            82.06  4.38                                                                    12.89               136                                                                                ##STR113##              47.0                                                                               isooctane  112-113                                                                              332(10,411)                                                                          C,65.18 H, 3.22                                                                N,13.41                                                                            65.03  3.10                                                                    13.62               137                                                                                ##STR114##              56.7                                                                               hexanes    105-107                                                                              329(20,354)                                                                          C,79.70 H, 6.35                                                                N,13.94                                                                            79.59  6.58                                                                    13.84               138                                                                                ##STR115##              37.2                                                                               isopropanol- toluene                                                                      149-150.5                                                                            334(22,650)                                                                          C,74.17 H, 4.76                                                                N,15.26                                                                            74.18  4.79                                                                    15.33               139                                                                                ##STR116##              51.5                                                                               isopropanol                                                                               136-138                                                                              329(16,600)                                                                          C,70.81 H, 4.95                                                                N,13.76                                                                            70.61  5.06                                                                    13.56               140                                                                                ##STR117##              31.5                                                                               ethanol    173-175                                                                              328(16,280)                                                                          C,68.70 H, 3.60                                                                N,15.02                                                                            69.06  3.28                                                                    15.08               141                                                                                ##STR118##              6.8 benzene- hexanes                                                                          166-168                                                                              331(10,300)                                                                          C,68.70 H, 3.60                                                                N,15.02                                                                            68.77  3.48                                                                    14.87               142                                                                                ##STR119##              35.2                                                                               isopropanol                                                                               133-134                                                                              330(14,000)                                                                          C,68.70 H, 3.60                                                                N,15.02                                                                            68.43  3.45                                                                    14.89               143                                                                                ##STR120##              61.9                                                                               toluene    215-217.5                                                                            333(16,530)                                                                          C,61.16 H, 2.89                                                                N,13.37                                                                            60.94  2.82                                                                    13.50               144                                                                                ##STR121##              3.4 carbon tetra- chloride                                                                    168-170                                                                              321(13,030)                                                                          C,61.17 H, 2.89                                                                N,13.37                                                                            60.61  2.85                                                                    13.57               145                                                                                ##STR122##              24.1                                                                               dimethylformamide- water                                                                  161.5-164.5                                                                          319(10,200)                                                                          C,59.28 H, 3.11                                                                N,12.96                                                                            58.75  3.03                                                                    12.90               146                                                                                ##STR123##              13.4                                                                               dimethylformamide- water                                                                  172   329(12,900)                                                                          C,59.28 H, 3.11                                                                N,12.96                                                                            59.34  3.13                                                                    13.23               147                                                                                ##STR124##              39.1                                                                               isopropanol                                                                               183-185                                                                              328(14,500)                                                                          C,72.99 H, 3.83                                                                N,15.96                                                                            73.00  4.06                                                                    15.77               148                                                                                ##STR125##              15.0                                                                               ethanol    190-192                                                                              222(48,000)                                                                          C,70.58 H, 3.83                                                                N,14.52                                                                            70.54  3.71                                                                    14.67               149                                                                                ##STR126##              53.3                                                                               dimethylformamide- water                                                                  257.5-259.5                                                                          335(14,900)                                                                          C,75.54 H, 3.73                                                                N,20.73                                                                            75.15  3.85                                                                    20.66               150                                                                                ##STR127##              59.8                                                                               2-ethoxyethanol                                                                           220.5-222.5                                                                          333(13,850)                                                                          C,66.20 H, 3.47                                                                N,19.30                                                                            66.10  3.48                                                                    19.53               151                                                                                ##STR128##              40.3                                                                               toluene    249-252                                                                              346(15,269)                                                                          C,66.20 H, 3.47                                                                N,19.30                                                                            66.10  3.44                                                                    19.28               152                                                                                ##STR129##              52.5                                                                               dimethylformamide                                                                         283-285                                                                              340(10,880)                                                                          C,57.30 H, 2.71                                                                N,20.89                                                                            57.08  2.74                                                                    21.11               153                                                                                ##STR130##              75.7                                                                               dimethylformamide- water                                                                  198-199.5                                                                            369(23,470)                                                                          C,73.83 H, 4.65                                                                N,21.53                                                                            73.48  4.69                                                                    21.54               154                                                                                ##STR131##              61.9                                                                               dimethylformamide- water                                                                  130-133                                                                              326(14,830)                                                                          C,73.83 H, 4.65                                                                N,21.53                                                                            73.56 4.78                                                                     21.69               155                                                                                ##STR132##              58.0                                                                               ethylacetate- hexane                                                                      214-217                                                                              342(27,700)                                                                          C,68.88 H, 4.66                                                                N,17.85                                                                            68.46  4.99                                                                    17.76               156                                                                                ##STR133##              13.9                                                                               dimethylformamide- water                                                                  237.5-240                                                                            345(32,350)                                                                          C,68.24 H, 3.90                                                                N,13.84                                                                            68.54  3.90                                                                    14.00               173                                                                                ##STR134##              32.3                                                                               ethanol    155-157                                                                              321(13,090)                                                                          C,72.99 H, 3.83                                                                N,15.96                                                                            72.44  3/83                                                                    16.14               157                                                                                ##STR135##              56.6                                                                               dimethylformamide- water                                                                  134.5-136                                                                            332(14,260)                                                                          C,59.28 H, 3.11                                                                N,12.96                                                                            59.25  3.04                                                                    13.11               158                                                                                ##STR136##              47.5                                                                               dimethylformamide- water                                                                  132.5-134                                                                            330(13,970)                                                                          C,72.99 H, 3.83                                                                N,15.96                                                                            73.00  3.79                                                                    15.84               159                                                                                ##STR137##              52.7                                                                               ethanol    113-114.5                                                                            329(16,500)                                                                          C,74.17 H, 4.76                                                                N,15.26                                                                            74.09  4.71                                                                    15.05               160                                                                                ##STR138##              10.62                                                                              chloroform 159-161.5                                                                            323((15,290)                                                                         C,81.34 H, 4.43                                                                N,14.23                                                                            81.29  4.41                                                                    14.22               161                                                                                ##STR139##              43.2                                                                               benzene    154.5-156.5                                                                          340(21,800)                                                                          C,81.34 H, 4.44                                                                N,14.23                                                                            81.19  4.57                                                                    13.92               162                                                                                ##STR140##              25.4                                                                               isopropanol                                                                               210-215                                                                              343(23,800)                                                                          C,68.81 H, 4.69                                                                N,15.04                                                                            68.99  4.63                                                                    14.92               163                                                                                ##STR141##              84.2                                                                               ethanol    158-160                                                                              333(14,950)                                                                          C,71.28 H, 4.32                                                                N,13.85                                                                            71.31  4.44                                                                    13.85               164                                                                                ##STR142##              80.3                                                                               ethanol    116-118                                                                              335(15,100)                                                                          C,72.49 H, 5.17                                                                N,12.68                                                                            72.38  5.42                                                                    12.36               165                                                                                ##STR143##              62.6                                                                               ethanol    90.5-93.5                                                                            335(15,100)                                                                          C,75.15 H, 7.03                                                                N,10.11                                                                            74.87  7.16                                                                    9.94                166                                                                                ##STR144##              45.85                                                                              chloroform 154-155.5                                                                            344(27,240)                                                                          C,76.38 H, 8.51                                                                N,11.14                                                                            76.58  8.35                                                                    10.81               193                                                                                ##STR145##              29.80                                                                              ethanol    150-152                                                                              342(22,900)                                                                          C,74.72 H, 5.23                                                                N,14.52                                                                            74.37  5.17                                                                    14.33               196                                                                                ##STR146##              8.2 dimethylformamide- water                                                                  178-181                                                                              330(27,300)                                                                          C,51.77 H, 2.72                                                                N,11.32                                                                            51.89  2.68                                                                    11.46               219                                                                                ##STR147##              37.1                                                                               toluene    151.5-153.5                                                                          333(21,000)                                                                          C,78.32 H, 4.48                                                                N,12.45                                                                            78.32 4.63                                                                     12.22               220                                                                                ##STR148##              35.1                                                                               benzene    151.5-153.5                                                                          337(22,200)                                                                          C,75.19 H, 4.66                                                                N,11.44                                                                            75.42  4.58                                                                    11.46               221                                                                                ##STR149##              33.3                                                                               ethanol-water                                                                             300-330                                                                              343(22,700)                                                                          C,72.92 H, 4.45                                                                N,11.60                                                                            73.21  4.31                                                                    11.74               222                                                                                ##STR150##              28.2                                                                               ethanol    83-85 348(24,600)                                                                          C,72.04 H, 5.74                                                                N,12.60                                                                            71.64  5.68                                                                    12.62               194                                                                                ##STR151##              22.6                                                                               toluene    164-165.5                                                                            339(19,400)                                                                          C,68.05 H, 5.11                                                                N,12.53                                                                            67.70  5.03                                                                    12.32               __________________________________________________________________________      Notes To Table VI:                                                             .sup.a U.S. Pat. No. 3,887,566 describes this compound as having a m.p. o      154-157° C.                                                             .sup.b Prepared by refluxing equimolar amounts of the                          2aminophenyl-imidazole and phthalic anlydride in toluene for one and one       half hours. Upon cooling, the product separated out of solution.               .sup.c Prepared by catalytic hydrogenation with 10% palladium on carbon o      a dimethylformamide solution of the nitro analog; crude product                precipitated with water.                                                       .sup.d Prepared by treating compound 153 in pyridine with the appropriate      acid chloride followed by precipitation with water.                            .sup.e Prepared by HI cleavage of compound No.138.                             .sup.f Prepared by treating the lithium salt of compound No. 162 with the      appropriate acid chloride in DMF followed by precipitation with water.         .sup.g Prepared by treating compound No. 151 with the appropriate              nucleophile according to the method of Kornblum et al, J. Org. Chem., 41,      1560(1976).                                                                    .sup.h Prepared by HI cleavage of compound 220.                          

The 4-Alkylaminoimidazo[1,2-a]quinoxalines (Table VII) were prepared by treating the corresponding alkylureylenes (Table III) with phosphorous oxychloride and pyridine during one-half hour at reflux temperatures. The reaction mixture was poured into cold water and the excess pyridine was removed by azeotropic distillation. The crude product was dissolved in chloroform and pass through an alumina columa. After evaporation of the chloroform, the solid was crystallized from the indicated solvent and obtained in the indicated yield.

                                      TABLE VII                                    __________________________________________________________________________      ##STR152##                                                                    4-Alkylaminoimidazo{1,2-a}quinoxalines                                                     %   Crystallization      Analysis                                  No.                                                                               R        Yield                                                                                Solvent                                                                              m.p. °C.                                                                      λmax. (Am)                                                                     Calc'd                                                                             Found                                 __________________________________________________________________________     167                                                                                ##STR153##                                                                             4.89                                                                               hexane  98.5-101.5                                                                           335(11,700)                                                                           C,72.15 H, 6.81 N,21.04                                                            72.02  6.75 20.81                     168                                                                               CH.sub.3 (CH.sub.2).sub.2 CH.sub.2                                                      28.33                                                                              isopropyl ether                                                                        102-104                                                                              332(11,480)                                                                           C,69.97                                                                            70.12                                                                      H, 6.71                                                                             6.71                                                                      N,23.31                                                                            23.21                                 169                                                                               CH.sub.3 (CH.sub.2).sub.2                                                               7.5 isopropyl ether                                                                        72-74 317(15,800)                                                                           C,69.00                                                                            69.14                                                                      H, 6.24                                                                             6.35                                                                      N,24.76                                                                            24.60                                 __________________________________________________________________________

4-Arylaminoimidazo[1,2-a]quinoxalines (Table VIII) were prepared by treating the corresponding arylureylenes (Table IV) with an equimolar amount of phosphorous oxychloride in refluxing pyridine during one hour. The cooled reaction mixture was stirred into cold water, and the crude solid which separated was dissolved in chloroform, dried and passed through an alumina column. The chloroform was evaporated and the crude solid crystallized as indicated in Table VIII.

                                      TABLE VIII                                   __________________________________________________________________________      ##STR154##                                                                    4-Arylaminoimidazo(1,2-a)quinoxalines                                                               %   Crystallization        Analysis                       No.                                                                               Ar                Yield                                                                              Solvent    m.p.°C.                                                                       λmax.(Am)                                                                     Calc'd                                                                             Found                      __________________________________________________________________________     170                                                                                ##STR155##        7.2                                                                               ethanol-water                                                                             120-123                                                                              304(13,800)                                                                          C,72.57 H, 4.76 N,21.16                                                            72.67  4.71 20.08          171                                                                                ##STR156##       13.1                                                                               methanol- chloroform                                                                      151   334(20.700)                                                                          C,74.43 H, 5.14 N,20.42                                                            74.16  5.06 20.09          172                                                                                ##STR157##       11.7                                                                               methanol- chloroform                                                                      153-155                                                                              330(20,200)                                                                          C,74.43  H, 5.14 N,20.42                                                           73.23  5.26 20.02          174                                                                                ##STR158##       13.6                                                                               methanol- chloroform                                                                      176.5-178                                                                            330(22,200)                                                                          C,65.26 H, 3.75 N,19.02                                                            65.04  3.77 18.91          175                                                                                ##STR159##       10.9                                                                               methanol- chloroform                                                                      178.5-180.5                                                                          344(33.600)                                                                          C,58.38 H, 3.06 N,17.02                                                            58.15  3.06 17.09          176                                                                                ##STR160##       18.2                                                                               toluene- chloroform                                                                       193.5-195                                                                            332(4,500)                                                                           C,49.76 H, 2.87 N,14.51                                                            49.72  3.10 14.39          177                                                                                ##STR161##       11.5                                                                               ethanol    196.5-198.5                                                                          324(16,600)                                                                          C,56.66 H, 3.27 N,16.52                                                            56.69  3.24 16.43          178                                                                                ##STR162##       15.0                                                                               methanol- chloroform                                                                      184-185.5                                                                            329(24,100)                                                                          C,56.66 H, 3.27 N,16.52                                                            56.26  3.20 16.54          179                                                                                ##STR163##       10.52                                                                              dimethylformamide water                                                                   122-124                                                                              343(19,600)                                                                          C,63.27  H, 3,98 N,18.45                                                           62.94  4.19 18.58          180                                                                                ##STR164##       13.0                                                                               ethanol-dimethyl- formamide                                                               139   339(19,810)                                                                          C,69.05 H, 3.98 N,20.13                                                            68.88  4.02 20.13          181                                                                                ##STR165##        9.4                                                                               isopropanol                                                                               148.5-149.5                                                                          343(20,230)                                                                          C,69.05 H, 3.98 N,20.13                                                            68.92  4.00 20.14          182                                                                                ##STR166##        3.1                                                                               isopropanol                                                                               139.5-141                                                                            331(18,030)                                                                          C,69.05 H, 3.98 N,20.13                                                            68.50 3.92 19.86           183                                                                                ##STR167##       16.58                                                                              dimethylformamide- water                                                                  166-168.5                                                                            347(21,730)                                                                          C,56.66 H, 3.27 N,16.52                                                            56.31  3.25 16.56          184                                                                                ##STR168##       11.4                                                                               dimethylformamide- water                                                                  207-209                                                                              366(22,410)                                                                          C,70.33 H, 4.86 N,19.30                                                            70.61  5.11 19.11          185                                                                                ##STR169##        8.3                                                                               dimethylformamide- water                                                                  116.5-11.7.5                                                                         335(21,820)                                                                          C,70.33 H, 4.86 N,19.30                                                            70.16  5.28  19.31         186                                                                                ##STR170##       14.12                                                                              dimethylformamide- water                                                                  147-149                                                                              339(18,540)                                                                          C,70.33 H, 4.86 N,19.30                                                            70.14  4.98 19.09          187                                                                                ##STR171##        2.0                                                                               isopropanol-dimethyl- formamide                                                           195-197                                                                              341(20,370)                                                                          C,60.28 H, 3.95 N,21.97                                                            60.21  3.88 21.63          188                                                                                ##STR172##       36.4                                                                               dimethylformamide- water                                                                  241-243.5                                                                            400(8,960)                                                                           C,62.95 H, 3.63 N,22.94                                                            62.62  3.63 22.68          186                                                                                ##STR173##       33.1                                                                               dimethylformamide- water                                                                  323-324.5                                                                            368(23,670)                                                                          C,62.95 H, 3.63 N,22.94                                                            62.73  3.73 22.81          195                                                                                ##STR174##       11.61                                                                              dimethylformamide- water                                                                  138.5-141                                                                            335(22,900)                                                                          C,74.99 H, 4.58 N,15.90                                                            75.02  4.66 75.02          197                                                                                ##STR175##        5.52                                                                              dimethylformamide- water                                                                  143-145                                                                              330(18,000)                                                                           C,74.43 H, 5.15 n,20.42                                                           74.63  5.16 20.09          198                                                                                ##STR176##       10.91                                                                              dimethylformamide                                                                         163.5-165.5                                                                          337(18,800)                                                                          C,74.98 H, 5.59 N,19.43                                                            74.69  5.56 19.43          199                                                                                ##STR177##       15.29                                                                              dimethylformamide- water                                                                  81-83 333(20,800)                                                                          C,73.83 H, 5.51 N,19.13                                                            73.87  5.49 18.88          200                                                                                ##STR178##       13.81                                                                              dimethylformamide- water                                                                  124.5-127                                                                            335(23,200)                                                                          C,73.83 H, 5.51 N,19.13                                                            74.14  5.47 19.02          201                                                                                ##STR179##       16.96                                                                              isopropanol- water                                                                        89.5-91.5                                                                            335(21,000)                                                                          C,73.83 H, 5.51 N,19.13                                                            74.14  5.47 19.02          202                                                                                ##STR180##       11.50                                                                              methanol- chloroform                                                                      187-190                                                                              342(24,200)                                                                          C,76.29 H, 4.56 N,17.00                                                            76.58  4.52  17.58         203                                                                                ##STR181##       12.50                                                                              dimethylformamide- water                                                                  120.5-123                                                                            340(20,300)                                                                          C,68.99 H, 5.15 N,17.88                                                            68.32  5.32 17.61          204                                                                                ##STR182##       21.39                                                                              dimethylformamide- water                                                                  102.5-107                                                                            340(19,600)                                                                          C,62.20 H, 3,38 N,17.07                                                            61.56  3,34 17.46          205                                                                                ##STR183##        8.5                                                                               dimethylformamide- water                                                                  90-97 341(26,400)                                                                          C,65.68 H, 4.62 N,18.02                                                            65.56  4.57 17.88          206                                                                                ##STR184##       21.39                                                                              dimethylformamide- water                                                                  129-130                                                                              347(20,300)                                                                          C,62.20 H, 3.38 N,17.07                                                            61.56  3.34 17.46          207                                                                                ##STR185##       11.49                                                                              dimethylformamide- water                                                                  178.5-179.5                                                                          324(25,500)                                                                           C,56.29 H, 2.78 N,15.45                                                           55.86  2.72 15.37          208                                                                                ##STR186##        7.52                                                                              dimethylformamide- water                                                                  172.5-173.5                                                                          345(24,900)                                                                          C,56.29 H, 2.78 N,15.45                                                            56.13  2.72 15.35          209                                                                                ##STR187##       15.18                                                                              dimethylformamide- water                                                                  170-172                                                                              332(23,800)                                                                          C,65.18 H, 4.18 N,17.89                                                            65.35  4.15 17.91          210                                                                                ##STR188##       13.56                                                                              dimethylformamide- water                                                                  171.5-173                                                                            337(17,300)                                                                          C,64.86 H, 3.40 N,18.91                                                            64.92  3.51 19.00          211                                                                                ##STR189##       10.78                                                                              dimethylformamide- water                                                                  259.5-261.5                                                                          342(23,200)                                                                          C,56.82 H, 3.28 N,16.57                                                            56.76  3.07 16.57          212                                                                                ##STR190##        7.22                                                                              dimethylformamide- water                                                                  198-200                                                                              343(18,400)                                                                          C,61.45 H, 3.22 N,17.92                                                             61.35  3.27 17.81         213                                                                                ##STR191##        3.04                                                                              methanol-chloroform                                                                       229-231                                                                              341(19,900)                                                                          C,58.63 H, 3.15 N,21.36                                                            58.50  3.06 21.20          214                                                                                ##STR192##        4.18                                                                              methanol-chloroform                                                                       168-170                                                                              344(21,400)                                                                          C,63.06 H, 4.12 N,21.63                                                            62.97  4.08 21.34          215                                                                                ##STR193##       19.43                                                                              dimethylformamide- water                                                                  271-273                                                                              346(19,600)                                                                          C,56.57 H, 2.97 N,20.61                                                            56.44  2.90 20.51          216                                                                                ##STR194##        5.96                                                                              dimethylformamide- water                                                                  224-226.5                                                                            349(34,700)                                                                          C,70.48 H, 3.91 N,24.17                                                            70.89  3.94 24.09          218                                                                                ##STR195##        2.31                                                                              isopropanol                                                                               95-96.5                                                                              --    C,75.47 H, 6.00 N,18.53                                                            75.08  6.34 18.53          __________________________________________________________________________

Various compounds of this invention display antifungal and anti-yeast activity. Thus, for example, they have been found to be effective against such organisms as Candida albicans (ATCC No. 10231), Candida tropicalis, Aspergillus niger (ATCC No. 16404), Trichophyton mentagrophytes (ATCC No. 8757 and 9129), Trichophyton rubrum (ATCC No. 10218 and 14001) and Trichophyton ajelloi.

The antifungal activity of compounds of this invention indicate their usefulness against dermatomycosis such as tinea capitis, tinea favosa, tinea barbae, tinea corporis, tinea imbricata, tinea cruris, tinea pedis, tinea manus, tinea unquium and various types of candidiasis such as glossitis, stomatitis, chelitis, perleche, vaginitis and balanitis.

When the compounds of the present invention are used for antifungal medical purposes, they will usually be incorporated in a suitable pharmaceutical carrier. These antifungal preparations may take the form of solutions, lotions, creams, ointments, etc. The quantity of antifungal agent of this invention that will be contained in such preparations may vary somewhat. Ordinarily, however, it will constitute about 0.5% to 10.0% by weight based on the total weight of the preparation.

In Table IX below are listed the antifungal activity of a number of compounds encompassed in the present invention. These were determined by the agar dilution method as described in Chapters 2 and 3 of Methods in Microbiology, Vol. 7B, edited by J. R. Norris and D. W. Ribbons, Academic Press, New York, 1972.

                  TABLE IX                                                         ______________________________________                                         Antifungal Activity                                                            Parts Per Million Inhibitions of                                               Fungus and Yeast Species                                                       Com-                                                                           pound  C.       C.       A.   T.    T. menta-                                                                             T.                                  No.    albicans tropicalis                                                                              niger                                                                               ajelloi                                                                              grophytes                                                                             rubrum                              ______________________________________                                         20                            100   100                                        136                                 100                                        40     100      100           100   100                                        35                            100   16                                         39                            100   100                                        133    100      100           8     8      8                                   134                           100   16                                         139                                 100                                        137                           100   100                                        135                           100   100                                        142                                 100                                        132                           100   100                                        138                           100   100                                        130    100      100           100   100                                        113    100      100                 100                                        9                                   16     16                                  10                                  16     16                                  116                                 16     16                                  127                                 16     16                                  109                                 128    32                                  114                                 16     1                                   118                                 256    4                                   123                                        2                                   131                                 16     2                                   140                                        <0.5                                151                                        1                                   119                                        8                                   120                                        1                                   8                                   8      8                                   16                                  4      2                                   110                      128        128    64                                  122                                        32                                  112                                 128    64                                  153             100                                                            124    100      100           100   100    8                                   58                            100   100    100                                 59                                         100                                 62                            100   100    100                                 126                           100   100    100                                 145                           100   100    100                                 159                           100   100    100                                 160                           100   100    100                                 163                           100   100    100                                 164                           100   100    100                                 165                           100   100    100                                 167                           100   100    100                                 168                           100   100    100                                 169                           100   100    100                                 173                           100   100    100                                 179                           100   100    100                                 182                                        100                                 184                           100   100    100                                 185                           100   100    100                                 186                           100   100    100                                 189                           100          100                                 187                           100          100                                 128                                        16                                  129                           16    16     8                                   ______________________________________                                    

A number of the compounds encompassed in the present invention have been found to have immunosuppressant action. Of those tested, most of these are of the 4-substituted imidazo[1,2-a]quinoxaline type described in formula I above, although a couple are of the 1-(2-acylaminophenyl)imidazole type shown in formula II. Because they exhibit this activity, they are indicated for use in the treatment of those diseases that the prior art recognizes may be helped by the administration of immunosuppressants. These include such conditions as- glomerulonephritis, serum sickness, organ transplant, rheumatoid arthritis, systemic lupus erythematosis, ulcerative colitis, chronic active hepatitis, multiple sclerosis, heterografts or homografts in burns, psoriatic arthritis, urticaria, respiratory allergies, i.e. asthma, hayfever; scleraclerma, mycosis fungoides, dermatomyositis, psoriasis and contact dermatitis (including poison ivy).

The dosage level for administering the immunosuppressants of the present invention will vary with the particular compound that is to be administered. In general, this will be at about the same level of the prior art immunosuppressants. For the most part, when the present immunosuppressants are administered orally or intraveneously, the daily dose would be in the range of about 0.1 mg. to 15 mg./per kilogram of body weight. When other mode of administration are employed, e.g. depot injections, implants, etc. the dose may be considerably higher i.e. up to about 100 mg./kg of body weight in a single injection.

The immunosuppressant activities of the compounds of this invention were determined via the hemolysin test in mice and by the delayed hypersensitivity test. The hemolysin test used is that described in Methods in Immunology, edited by D. H. Campbell et al, W. A. Benjamin, New York 1963 pages 172-175, and measures humeral or antibody response. The delayed hypersensitivity test measures the effect of a test compound on the ability of a subject mouse to mount a cell-mediated immune response to the antigen, Mycobacterium tuberculosis H37Ra. The mouse is sensitized to the antigen by subcutaneous administration in the base of the tail. The development of the delayed hypersensitivity response may be measured at any time beginning six days after sensitization but is usually done on the ninth day as follows: The right hind paw is injected with purified protein derivative (tuberculin) while the left hind paw (control) receives physiological saline. Both paw volumes are measured after twenty-four hours and significant increase in the volume of the right hand paw is taken as a measure of an effective delayed hypersensitivity response. All compounds were administered by the subcutaneous route.

The results of these studies are summarized in Table X below. The expression HL(ED₅₀) mg./kg. s.c. is an expression of the number of milligrams per kilogram of body weight of the drug administered subcutaneously required to reduce the antibody activity by 50% when compared with a control. In this case, the lower the HL(ED₅₀) value for a drug the more effective immunosuppressant it is.

The D.H.S. (ED₆₀) mg./kg. s.c. value appearing in column 3 is an expression of the effectiveness of the drug in reducing the edema that accompanies the cell-mediated immune response. It is a measure of the number of milligrams per kilogram of body weight of the drug administered subcutaneously which is required to reduce the edema of the cell-mediated immune response by 60% when compared to the control. Again, the lower the D.H.S. (ED₆₀) value the more effective is the drug as an immunosuppressant for the cell-mediate immune response.

                  TABLE X                                                          ______________________________________                                         Compound     HL(ED.sub.50)                                                                               D.H.S. (ED.sub.60)                                   No.          mg/kg, s.c.  mg/kg, s.c.                                          ______________________________________                                         151          0.3          1.52                                                 140          0.26         1.15                                                 131          18           81                                                   116          >50          56                                                   117          >50          46                                                   118          >50          43                                                   109          >50          >50                                                  110          --           50                                                   3            50           50                                                   66           46           >50                                                  147          0.027        1.7                                                  134          0.5          7.2                                                  137          <0.125       3.2                                                  135          0.033        0.22                                                 142          0.20         4.2                                                  136          2.7          >50                                                  133          0.75         32                                                   139          3.0          >50                                                  138          0.72         27                                                   127          >50          36                                                   170          6.6          >50                                                  150          22           >50                                                  143          0.36         1.3                                                  174          0.61         8.0                                                  171          0.96         59.0                                                 175          0.09         5.9                                                  178          11.0         46.0                                                 196          0.42         45.0                                                 197          1.6          37                                                   3            50.0         50.0                                                 169          46           >50.0                                                146          0.11         3.1                                                  153          1.2          5.7                                                  149          0.16         8.8                                                  126          35.0         >50.0                                                177          13.0         >50.0                                                182          1.1          --                                                   162          13.0         --                                                   173          --           40                                                   159          3.0          27                                                   181          16.0         --                                                   180          5.6          --                                                   183          0.39         15                                                   158          1.0          7.6                                                  157          0.39         12                                                   218          1.5          25                                                   219          2.5          >32                                                  220          2.3          11                                                   222          1.0          > 32                                                 ______________________________________                                          >50 means that it would take more than 50 mg./kg. of drug to reduce the        humeral antibody activity by 50% or to reduce edema of the cell mediated       immune response by 60%. Since these values are higher than is of practica      interest from a clinical point of view, no further testing was done for        these materials.                                                         

A number of compounds encompassed in the present invention display non-steroidal anti-inflammatory properties. This appears to be generally the case for the 4-substituted imidazo[1,2-a]quinoxalines of formula 1 above and the 1-(2-acylaminophenyl)imidazoles of formula II. Because of this characteristic, they are indicated for use in the treatment of diseases that the prior art recognizes may be helped by the administration of non-steroidal anti-inflammatory compounds. These include such conditions as ichthyosis, psoriasis, alopecia, atopic eczemas, etc.

The dosage level for administering the anti-inflammatory agents of the present invention may vary somewhat depending on the particular drug selected, the disease being treated and the mode of administration. In general, however, when used for topical application, the compounds are distributed in a pharmaceutical vehicle suitable for topical application. In these compositions, the anti-inflammatory agent of this invention will comprise about 0.5% to 15.0% by weight based on the total weight of the composition.

The anti-inflammatory agents of the present invention may also be administered orally, intravenously, subcutaneously, intramuscularly, and intradermally. In these cases, the daily dosage will be in the range of from 0.5 mg. to 20 mg. per kilogram of body weight of the active anti-inflammatory agents of this invention.

The anti-inflammatory activity of representative compounds of this invention was determined by the rat paw edema assay both by local administration (Table XI below) and by oral dosing (Table XII below). For the oral dosing, the procedure of C. A. Winter, E. A. Risley and G. W. Nuss, Proc. Soc. Exp. Biol. Med. 111, 544 (1962) was employed with measurement taken four hours after the drug was administered. The local administration tests were carried out similarly except the irritant (carrageenan) and the test compound were injected simultaneously at time zero.

Tables XI and XII report the anti-inflammatory activity of the compounds tested as % difference in the edema or swelling as compared with the control. These Tables also give the response in many instances of more than one dose level of the same drug.

                  TABLE XI                                                         ______________________________________                                         Rat Paw Edema Assay,                                                           Local Administration                                                           (injected directly into paw)                                                   % Difference from Control                                                      Compound No.                                                                              1μg   10μg  100μg                                                                               100 mg/kg                                 ______________________________________                                         148        -32.6    -53.5    -14.3   -39                                       109        -30.8     -3.9    +31.6                                             114        -68.2    -30.0    -131.6                                            117                                                                            110                                  -74                                       122                                  -61                                       49                                   -35                                       7                                    -22                                       51                                   -57                                       140                                  -78                                       ______________________________________                                    

                  TABLE XII                                                        ______________________________________                                         Rat Paw Edema Assay, Oral Dosing                                                            %Difference from Control                                          Compound No.   100 mg/kg    400 mg/kg                                          ______________________________________                                         Indomethacin   -65                                                             phenybutazone  -76                                                             Aspirin        -57                                                             114            -61                                                             110            -43                                                             122            -61                                                             148            -52                                                             49             -35                                                             7              -52                                                             51             -57                                                             140            -35                                                             131            -52                                                             10             -30                                                             39             -50                                                             133            -17                                                             137            -26                                                             112            -17          -68                                                111            -43                                                             121            -61                                                             147            -39                                                             134            -43                                                             139            -22          -25                                                132            -76                                                             150            -30                                                             144            -26                                                             115            +70          -25                                                117            -7           -18                                                123            0            -50                                                116            +104         -18                                                136            -9           -25                                                8              -22          -13                                                29             -24          -25                                                14             -52                                                             20             -59                                                             38             -41                                                             57             -35                                                             50             -20          -33                                                45             -33                                                             40             -43                                                             35             -50                                                             37             -35                                                             18             -28                                                             15             -24          -5                                                 55             -26                                                             52             -26                                                             2              -26          +43                                                23             -46                                                             25             -30                                                             30             + 9          -33                                                36             -7           -68                                                42             -9           -25                                                24             -17          -25                                                109            -17                                                             71             -22                                                             75             -30                                                             68             -26                                                             73             -22                                                             128            -39                                                             129            -30                                                             ______________________________________                                     

What is claimed is:
 1. A process for preparing 4-substituted imidazo [1,2-a]quinoxalines of the formula: ##STR196## which comprises reacting, at a temperature of from about 95° C. to 195° C., a 1-(2-acyl aminophenyl)imidazole of the formula: ##STR197## with a cyclizing amount of a cyclizing agent selected from the group consisting of phosphorus oxychloride and polyphosphoric acid to produce said 4-substituted imidazo [1,2-a]quinoxaline in which --X² is --R⁵ or --NHR² wherein:(1) R⁵ is hydrogen or a straight chain or branched hydrocarbon aliphatic group of from 1 to 18 carbon atoms; cycloalkyl of from 3 to 8 carbon atoms or cyclo alkenyl of 5-6 carbon atoms; phenyl; mono- or di-substituted phenyl which is substituted by alkyl of from 1 to 6 carbon atoms, alkoxyl of from 1 to 6 carbon atoms, halogen, trifluoromethyl, phenoxy, alkylthio, nitro, cyano or phenyl; napthyl; phenoxymethyl; benzyl; or styryl; and (2) R² is a radical bonded to the nitrogen by a carbon to nitrogen linkage and selected from the group consisting of aliphatic of from 1 to 17 carbon atoms; cycloaliphatic of from 3 to 8 carbon atoms; phenyl; mono- or di-substituted phenyl substituted with alkyl of from 1 to 6 carbon atoms, alkoxyl, of from 1 to 6 carbon atoms, alkanoyloxy of from 1 to 18 carbon atoms, halogen, nitro, cyano, trifluoromethyl, alkylthio, phenyl or phenoxy; napthyl; phenoxymethyl; styryl; and benzyl.
 2. The process according to claim 1 in which --X² is --R⁵.
 3. The process according to claim 2 in which --R⁵ is hydrogen.
 4. The process according to claim 2 in which --R⁵ is aliphatic.
 5. The process according to claim 2 in which --R⁵ is cycloaliphatic.
 6. The process according to claim 2 in which --R⁵ is phenyl or substituted phenyl.
 7. The process according to claim 2 in which --R⁵ is napthyl.
 8. The process according to claim 2 in which --R⁵ is benzyl.
 9. The process according to claim 1 in which --X² is --NHR².
 10. The process according to claim 9 in which R² is hydrogen.
 11. The process according to claim 9 in which R² is aliphatic.
 12. The process according to claim 9 in which R² is cycloaliphatic.
 13. The process according to claim 9 in which R² is phenyl or substituted phenyl.
 14. The process according to claim 9 in which R² is napthyl.
 15. The process according to claim 9 in which R² is benzyl.
 16. The process according to claim 1 further including the step of recovering the produced 4-substituted imidazo [1,2-a]quinoxaline.
 17. The process according to claim 1 wherein the reaction is carried out in an organic amine solvent.
 18. The process according to claim 17 wherein said solvent is selected from the group consisting of pyridine, 2,6-dimethylpyridine, N,N-dimethylanaline, trimethylamine and N-methylmorpholine.
 19. The process according to claim 1 wherein the cyclizing agent is phosphorous oxychloride.
 20. The process according to claim 19 wherein from about 1/2 to 6 moles of the phosphorous oxychloride are employed per mole of said 1-(2-acyl amino phenyl) imidazole compound.
 21. The process according to claim 19 wherein 1/2 to 2 moles of the phosphorous oxychloride are employed per mole of said 1-(2-acylamino phenyl) imidazole compound.
 22. The process according to claim 1 wherein said reacting step is carried out for from about 30 to 120 minutes.
 23. The process according to claim 1 wherein said reacting step is carried out at reflux temperature.
 24. The process according to claim 1 wherein said cyclizing agent is polyphosphoric acid. 